Work

IFN-γ-driven UBE2D3 upregulation impairs antigen presentation pathways and anti-tumor immunity in pancreatic cancer

Year: 2025

Type: article

Abstract: Although ubiquitin-conjugating enzymes are critical regulators of cellular function and fate, their roles in tumorigenesis remain incompletely defined. Here, we provide genetic and molecular evidence that the Ubiquitin-Conjugating Enzyme E2 D3 (UBE2D3) is specifically overexpressed in cancerous pancreatic ductal cells, including early-stage pancreatic intraepithelial neoplasia and advanced pancreatic ductal adenocarcinoma (PDAC). This overexpression is independent of oncogenic KRAS status and is driven by the inflammatory tumor microenvironment, particularly interferon-γ (IFN-γ). Mechanistically, UBE2D3 binds the ubiquitin ligase Kelch Like Family Member 13 (KLHL13) to mediate K63-linked polyubiquitination at lysine 245 of transporter 2 (TAP2), resulting in steric hindrance that blocks the transporter. Genetic or pharmacologic inhibition of UBE2D3 enhances antigen presentation in cancer cells and restores CD8+ T-cell-mediated tumor surveillance in pancreatic cancer models in male mice. Furthermore, combining an UBE2D3 small-molecule inhibitor with KRASG12D-specific TCR-T-cell therapy yields synergistic antitumor effects. Our findings reveal a negative feedback mechanism in which cancer cells, “camouflaging” themselves, evade IFN-γ-induced antigen presentation via UBE2D3 upregulation, highlighting a potential therapeutic target for enhancing antitumor immunity. Ubiquitin-conjugating enzymes (E2s), including UBE2D3, are important regulator of cellular function and fate. Here the authors report that IFN-y driven upregulation of UBE2D3 is associated with impaired antigen presentation in pancreatic cancer, also showing that its targeting enhances antitumor immunity.

Source: Nature Communications

DOI: 10.1038/s41467-025-65762-4